21 results on '"Karissa Finke"'
Search Results
2. Supplementary section from Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Andrew K. Godwin, Qamar J. Khan, Bruce F. Kimler, Gregory A. Reed, Milind A. Phadnis, Stephen K. Williamson, Stephanie LaFaver, Jaimie Heldstab, Karissa Finke, Kelsey Schwensen, Rachel Yoder, Yen Y. Wang, Jilliann A. De Jong, Jecinta Scott, Sharon Lewis, Manana Elia, Shane R. Stecklein, Marc Hoffmann, Harsh B. Pathak, Ingrid Mayer, Lauren Nye, Anne O'Dea, Vandana G. Abramson, and Priyanka Sharma
- Abstract
Supplementary text
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- 2023
3. Figure S1 from Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP)
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Qamar Khan, Kathan Mehta, Roberto Salgado, Andrew K. Godwin, Roy A. Jensen, Dinesh Pal Mudaranthakam, Milind Phadnis, Micki Prager, Stephanie LaFaver, Jaimie Heldstab, Larry Corum, Venkatadri Beeki, Vinay Raja, Robert Pluenneke, Richard McKittrick, Larry Beck, Anuj Shrestha, Deepti Satelli, Rajvi Shah, Karissa Finke, Roberto Rodriguez, Maureen Sheehan, Marc Hoffmann, Sheshadri Madhusudhana, Gregory Crane, Manana Elia, Christa Balanoff, Kelsey Larson, Amanda L. Amin, Jamie Wagner, Lindsey Prochaska, Joshua M. Staley, Rachel Yoder, Yen Y. Wang, Lauren Nye, Anne O'Dea, Bruce F. Kimler, and Priyanka Sharma
- Abstract
NeoSTOP study schema
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- 2023
4. Data from Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP)
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Qamar Khan, Kathan Mehta, Roberto Salgado, Andrew K. Godwin, Roy A. Jensen, Dinesh Pal Mudaranthakam, Milind Phadnis, Micki Prager, Stephanie LaFaver, Jaimie Heldstab, Larry Corum, Venkatadri Beeki, Vinay Raja, Robert Pluenneke, Richard McKittrick, Larry Beck, Anuj Shrestha, Deepti Satelli, Rajvi Shah, Karissa Finke, Roberto Rodriguez, Maureen Sheehan, Marc Hoffmann, Sheshadri Madhusudhana, Gregory Crane, Manana Elia, Christa Balanoff, Kelsey Larson, Amanda L. Amin, Jamie Wagner, Lindsey Prochaska, Joshua M. Staley, Rachel Yoder, Yen Y. Wang, Lauren Nye, Anne O'Dea, Bruce F. Kimler, and Priyanka Sharma
- Abstract
Purpose:Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens.Patients and Methods:Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS).Results:One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02).Conclusions:The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.
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- 2023
5. Data from Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Andrew K. Godwin, Qamar J. Khan, Bruce F. Kimler, Gregory A. Reed, Milind A. Phadnis, Stephen K. Williamson, Stephanie LaFaver, Jaimie Heldstab, Karissa Finke, Kelsey Schwensen, Rachel Yoder, Yen Y. Wang, Jilliann A. De Jong, Jecinta Scott, Sharon Lewis, Manana Elia, Shane R. Stecklein, Marc Hoffmann, Harsh B. Pathak, Ingrid Mayer, Lauren Nye, Anne O'Dea, Vandana G. Abramson, and Priyanka Sharma
- Abstract
Purpose:PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and Methods:Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.Results:A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.Conclusions:The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
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- 2023
6. Supplementary Figure 2 from Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Andrew K. Godwin, Qamar J. Khan, Bruce F. Kimler, Gregory A. Reed, Milind A. Phadnis, Stephen K. Williamson, Stephanie LaFaver, Jaimie Heldstab, Karissa Finke, Kelsey Schwensen, Rachel Yoder, Yen Y. Wang, Jilliann A. De Jong, Jecinta Scott, Sharon Lewis, Manana Elia, Shane R. Stecklein, Marc Hoffmann, Harsh B. Pathak, Ingrid Mayer, Lauren Nye, Anne O'Dea, Vandana G. Abramson, and Priyanka Sharma
- Abstract
Kaplan-Meier estimates of progression-free survival by baseline metabolic status
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- 2023
7. Supplementary Figure 3 from Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Andrew K. Godwin, Qamar J. Khan, Bruce F. Kimler, Gregory A. Reed, Milind A. Phadnis, Stephen K. Williamson, Stephanie LaFaver, Jaimie Heldstab, Karissa Finke, Kelsey Schwensen, Rachel Yoder, Yen Y. Wang, Jilliann A. De Jong, Jecinta Scott, Sharon Lewis, Manana Elia, Shane R. Stecklein, Marc Hoffmann, Harsh B. Pathak, Ingrid Mayer, Lauren Nye, Anne O'Dea, Vandana G. Abramson, and Priyanka Sharma
- Abstract
Gene expression signatures by PIK3CA mutation status
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- 2023
8. Supplementary Figure 1 from Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Andrew K. Godwin, Qamar J. Khan, Bruce F. Kimler, Gregory A. Reed, Milind A. Phadnis, Stephen K. Williamson, Stephanie LaFaver, Jaimie Heldstab, Karissa Finke, Kelsey Schwensen, Rachel Yoder, Yen Y. Wang, Jilliann A. De Jong, Jecinta Scott, Sharon Lewis, Manana Elia, Shane R. Stecklein, Marc Hoffmann, Harsh B. Pathak, Ingrid Mayer, Lauren Nye, Anne O'Dea, Vandana G. Abramson, and Priyanka Sharma
- Abstract
Kaplan-Meier estimates of overall survival
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- 2023
9. Abstract P4-10-03: Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer
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Cory Bivona, Kevin Li, Priyanka Sharma, Jianghua He, Grace Martin, Andrew K Godwin, Anthony Rooney, Stephen Williamson, Gary Doolittle, Weijing Sun, Bruce F Kimler, Anne P O'Dea, Lauren E Nye, Joseph P McGuirk, Ziyan Pessetto, Lisa Haney, Nicole Balmaceda, Laura Mitchell, Karissa Finke, Maggie Nelson, Dinesh Pal Mudaranthakam, Natalie Streeter, Stephanie Lafaver, Jaimie Heldstab, and Qamar J Khan
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Cancer Research ,Oncology - Abstract
Background: Infection with SARS-CoV-2 has led to a global pandemic and has significantly impacted the care of cancer patients. Breast cancer patients receiving active systemic therapy need protection against COVID19 but the efficacy of vaccines in this population is unknown. Although specific biomarkers associated with protection from SARS-CoV-2 infection have yet to be identified, measurement of serum antibody activity is generally accepted as a surrogate of in vivo humoral response to vaccine. This study evaluates the efficiency and durability of binding antibodies to SARS-CoV-2 spike (S) protein in response to COVID19 vaccine in breast cancer patients receiving systemic treatment. Methods: Breast cancer patients, who were unvaccinated, partially or fully vaccinated with Pfizer-BioNTech BNT162b2 (PF), Moderna mRNA-1273 (Mod) or Johnson & Johnson AD26.COV2.S (J&J) were enrolled in this prospective longitudinal study. Eligible patients were on systemic treatment with cytotoxic chemotherapy, chemotherapy plus a checkpoint inhibitor (CPI), CPI alone or a CDK 4/6 inhibitor. Longitudinal blood samples are being collected at baseline, prior to vaccination in unvaccinated patients (T0), 2 weeks after the first vaccine dose and before the second dose for the mRNA vaccines (T1), 1 month (T2), 3 months (T3), 6 months (T4) and 12 month post vaccination. For J&J, there was no T1 timepoint. Roche Elecsys® Anti-SARS-CoV-2 S receptor binding domain (RBD) antibody immunoassay was used to measure antibody titers (range 0.4 to 250 U/mL). Cut points of N% Seropositive (>0.8 U/mL)Mean Antibody Levels (U/mL)T0T1T2T3T0T1T2T3All subjects7510789810012.6102.3204.4214.6Chemotherapy50577961003.3105.6200.0250CDK 4/6 inhibitors15257510010013.786.8234.7205.8CPI + Chemotherapy82583100NA*62.8121.4177.5NA*CPI therapy20100100NA*0.46.82250NA*CPI=Checkpoint Inhibitors; *Timepoint for longitudinal samples not reached Citation Format: Cory Bivona, Kevin Li, Priyanka Sharma, Jianghua He, Grace Martin, Andrew K Godwin, Anthony Rooney, Stephen Williamson, Gary Doolittle, Weijing Sun, Bruce F Kimler, Anne P O'Dea, Lauren E Nye, Joseph P McGuirk, Ziyan Pessetto, Lisa Haney, Nicole Balmaceda, Laura Mitchell, Karissa Finke, Maggie Nelson, Dinesh Pal Mudaranthakam, Natalie Streeter, Stephanie Lafaver, Jaimie Heldstab, Qamar J Khan. Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-03.
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- 2022
10. Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP)
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Vinay Raja, Micki Prager, Marc Hoffmann, Qamar J. Khan, Sheshadri Madhusudhana, Larry Beck, Lauren Nye, Rajvi H. Shah, Jaimie Heldstab, Dinesh Pal Mudaranthakam, Stephanie LaFaver, Roy A. Jensen, Roberto Rodríguez, Kelsey E. Larson, Gregory James Crane, Amanda L. Amin, Richard McKittrick, Venkatadri Beeki, Joshua M Staley, Lindsey Prochaska, Roberto Salgado, Maureen Sheehan, Rachel Yoder, Andrew K. Godwin, Manana Elia, Bruce F. Kimler, Larry Corum, Anuj Shrestha, Priyanka Sharma, Kathan Mehta, Christa R. Balanoff, Deepti Satelli, Jamie L. Wagner, Anne O'Dea, Milind A. Phadnis, Robert Pluenneke, Yen Y. Wang, and Karissa Finke
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Adult ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Cyclophosphamide ,Anthracycline ,medicine.medical_treatment ,Triple Negative Breast Neoplasms ,Gastroenterology ,Article ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Anthracyclines ,Mastectomy ,Aged ,Neoplasm Staging ,Chemotherapy ,Taxane ,business.industry ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Progression-Free Survival ,Regimen ,030104 developmental biology ,Oncology ,chemistry ,Docetaxel ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Purpose: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. Patients and Methods: Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). Results: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). Conclusions: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.
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- 2021
11. Abstract P2-08-16: Impact of germline BRCA mutation status on survival in women with metastatic triple negative breast cancer
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Lauren Nye, Qamar J. Khan, Andrew K. Godwin, Bruce F. Kimler, Anne O'Dea, Kelsey E. Larson, J Heldstab, P Sharma, Yen Y. Wang, and Karissa Finke
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Breast surgery ,medicine.medical_treatment ,BRCA mutation ,Cancer ,medicine.disease ,Metastatic breast cancer ,Primary tumor ,Breast cancer ,Median follow-up ,Internal medicine ,medicine ,business ,Triple-negative breast cancer - Abstract
Background: 15-20% of patients with triple negative breast cancer (TNBC) harbor deleterious germline (g) BRCA1/2 mutations. Recent data suggests that in metastatic TNBC (mTNBC) gBRCA1/2 mutations are associated with response to PARP inhibitors (PARPi) and platinum chemotherapy. However, diagnosis of mTNBC is associated with short overall survival (OS) with no available biomarkers that can identify mTNBC patients with better prognosis. Aim: Utilizing data from a prospective registry, the objective of this study was to investigate whether presence of gBRCA1/2 mutation impacts overall survival for patients with mTNBC treated prior to clinical availability of PARPi. Methods: 643 patients with stage I-IV TNBC were enrolled in an IRB approved multisite prospective registry between 2011 to 2018. Clinical, demographic, and treatment information was collected and patients were followed for recurrence and survival. 100/643 patients had metastatic breast cancer (de novo stage IV disease or metastatic recurrence). OS (from the time of diagnosis of metastatic disease to death from any cause) was estimated according to the Kaplan-Meier method and compared among groups by log-rank test. Results: For the 100 mTNBC patients, the median age at diagnosis of metastatic disease was 55 years, 17% were African American, 20% had novo stage IV and 80% had relapsed disease. 84% had visceral disease, 12% had bone-only disease, and 4% had lymph node only disease. Metastatic treatment: 87% received chemotherapy, 7% received radiation only without chemotherapy and 6% did not receive any treatment. No patients received treatment with PARP inhibitor. Among de-novo stage IV patients, 35% (7/20) had breast surgery for removal of primary tumor during their course of metastatic treatment. For all 100 patients, 12% (n=12) had gBRCA mutation; 72% (n=72) had no gBRCA mutation; and 16% (n=16) had unknown BRCA mutation status. When compared with non-carriers, gBRCA carriers were younger at time of metastatic diagnosis (median age 49 vs. 57 years, p=0.02). There was no difference in prevalence of visceral disease, de-novo stage IV disease or median lines of metastatic chemotherapy among gBRCA carriers and non-carriers. At a median follow up of 31 months, median OS for all patients is 21 months (95% CI 13-23 months). Median OS is 18 months (95% CI 15-27 months) for non-carriers and has not yet been reached for gBRCA mutation carriers (p=0.023). 3-year estimated OS is 63% in gBRCA carriers compared to 28% in non-carriers (p=0.02). On multivariate Cox regression analysis, gBRCA carrier status was associated with reduced risk of death (HR=0.33; 95%CI [0.23-0.91], p=0.033) Conclusions: gBRCA mutation associated mTNBC patients have a clinically significant improved OS at 3 years compared to mTNBC patients without BRCA mutations (3-year OS of 63% vs 28%). Further research is needed to understand tumor and host biological reasons for this observation. Outcomes of gBRCA mutation associated mTNBC are likely to be further improved with availability of PARPi. Given that patients with gBRCA mutation are at risk for second breast/ovarian cancers, these findings also underscore need for further research regarding the role of prophylactic surgeries mTNBC with gBRCA mutation. Citation Format: Larson K, Wang YY, Finke K, O'Dea AP, Khan Q, Nye L, Heldstab J, Godwin AK, Kimler BF, Sharma P. Impact of germline BRCA mutation status on survival in women with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-16.
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- 2019
12. Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer
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Yen Y. Wang, Stephen K. Williamson, Karissa Finke, Jecinta Scott, Bruce F. Kimler, Priyanka Sharma, Andrew K. Godwin, Gregory A. Reed, Marc Hoffmann, Shane R. Stecklein, Rachel Yoder, Lauren Nye, Anne O'Dea, Qamar J. Khan, Sharon Lewis, Milind A. Phadnis, Stephanie LaFaver, Jaimie Heldstab, Jilliann A De Jong, Ingrid A. Mayer, Manana Elia, Vandana G Abramson, Harsh B. Pathak, and Kelsey Schwensen
- Subjects
0301 basic medicine ,Adult ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Class I Phosphatidylinositol 3-Kinases ,Receptor, ErbB-2 ,Breast Neoplasms ,Neutropenia ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Pharmacokinetics ,Internal medicine ,Albumins ,Biomarkers, Tumor ,Medicine ,Humans ,Neoplasm Metastasis ,Adverse effect ,Aged ,Taxane ,business.industry ,Middle Aged ,medicine.disease ,Rash ,Metastatic breast cancer ,Drug Combinations ,Thiazoles ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Mutation ,Female ,medicine.symptom ,business - Abstract
Purpose:PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and Methods:Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.Results:A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.Conclusions:The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
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- 2020
13. Effects of substituent size and linker orientation on LAT1-targeted amino acid prodrugs
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Hannah Way, Claire Colas, Seth Springer, Cesar Alvarado, Kasey Merklin, Surabhi Chandra, Joseph Griffith, Avner Schlessinger, Laura Stoner, Allen Thomas, Kathleen Giacomini, Huan-Chieh Chien, Huy Ngo, Brooklynn Venteicher, Evan Hill, and Karissa Finke
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- 2020
14. Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)
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Jerome Campbell, Seth Springer, Karissa Finke, Dimitrios Fotiadis, Arik A. Zur, Colton Hall, Andrew Flint, Nathan Heeren, Avner Schlessinger, Brooklynn Venteicher, Allen A. Thomas, Kathleen M. Giacomini, Logan Hansen, Justine Bauer, Abby Anthony, Claire Colas, Evan Augustyn, Christopher Hernandez, Huan-Chieh Chien, and Laura Stoner
- Subjects
0301 basic medicine ,Amino Acid Transport Systems ,Stereochemistry ,Phenylalanine ,1.1 Normal biological development and functioning ,Medicinal & Biomolecular Chemistry ,Stereoisomerism ,Ligands ,Article ,Antiporters ,Large Neutral Amino Acid-Transporter 1 ,Substrate Specificity ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Underpinning research ,Drug Discovery ,Humans ,Structure–activity relationship ,610 Medicine & health ,Histidine ,Structural Homology ,Cancer ,chemistry.chemical_classification ,Chemistry ,Escherichia coli Proteins ,Protein ,Organic Chemistry ,Neurosciences ,Pharmacology and Pharmaceutical Sciences ,Prodrug ,Amino acid ,Molecular Docking Simulation ,HEK293 Cells ,030104 developmental biology ,Structural Homology, Protein ,030220 oncology & carcinogenesis ,Drug delivery ,570 Life sciences ,biology ,Molecular Medicine ,Enantiomer - Abstract
The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood—brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand—transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure—activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
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- 2018
15. Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC)
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Anne O'Dea, Milind A. Phadnis, Gregory A. Reed, Ingrid A. Mayer, Kelsey Schwensen, Gregory James Crane, Stephen K. Williamson, Priyanka Sharma, Micki Prager, Karissa Finke, Andrew K. Godwin, Manana Elia, Vandana G. Abramson, Qamar J. Khan, Lauren Nye, Joshua M Staley, Rachel Yoder, Bruce F. Kimler, Stephanie LaFaver, and Jaimie Heldstab
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Cisplatin ,Cancer Research ,business.industry ,Antigen presentation ,Romidepsin ,Oncology ,Downregulation and upregulation ,Cancer research ,Medicine ,In patient ,Histone deacetylase ,Nivolumab ,business ,Triple-negative breast cancer ,medicine.drug - Abstract
1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]
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- 2021
16. Abstract PS6-04: Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2 negative breast cancer
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Bruce F. Kimler, Larry Corum, Roberto Rodríguez, Gregory James Crane, Priyanka Sharma, Manana Elia, Richard McKittrick, Qamar Khan, Sheshadri Madhusudhana, Lauren Nye, Anne O'Dea, Joshua M Staley, Andrew K. Godwin, Anuj Shrestha, Larry Beck, Rachel Yoder, Robert Pluenneke, Mark Marsico, Yen Y. Wang, Karissa Finke, and Kelsey Schwensen
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,medicine ,Estrogen+Progesterone receptor ,HER2 negative ,business ,medicine.disease - Abstract
Background: Triple negative breast cancer is defined by lack of expression of ER/PR (immunohistochemistry expression Table 1. Demographic, clinical, pathologic, and treatment characteristicsCharacteristics - N (%)All N=516TNBC (ER & PR Citation Format: Rachel Yoder, Bruce F Kimler, Joshua M Staley, Kelsey Schwensen, Yen Y Wang, Karissa Finke, Anne O'Dea, Lauren Nye, Manana Elia, Gregory Crane, Richard McKittrick, Robert Pluenneke, Sheshadri Madhusudhana, Larry Beck, Roberto Rodriguez, Anuj Shrestha, Larry Corum, Mark Marsico, Andrew K Godwin, Qamar Khan, Priyanka Sharma. Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2 negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-04.
- Published
- 2021
17. Impact of Germline BRCA Mutation Status on Survival in Women with Metastatic Triple Negative Breast Cancer
- Author
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Qamar Khan, Andrew K. Godwin, Rachel Yoder, Kelsey E. Larson, Anne O'Dea, Yen Y. Wang, Bruce F. Kimler, Karissa Finke, Lauren Nye, Priyanka Sharma, Kelsey Schwensen, and Jaimie Heldstab
- Subjects
Oncology ,medicine.medical_specialty ,Multivariate analysis ,Proportional hazards model ,business.industry ,BRCA mutation ,medicine.disease ,Breast cancer ,Internal medicine ,PARP inhibitor ,medicine ,Stage (cooking) ,business ,Disease burden ,Triple-negative breast cancer - Abstract
Purpose: To investigate the association between germline deleterious BRCA1 or BRCA2 mutations (gBRCA+) and overall survival (OS) for patients with metastatic triple negative breast cancer (mTNBC). Methods: An IRB approved prospective multisite registry enrolling stage I-IV TNBC patients from 2011-2018 was utilized. Demographics, treatments, genetic results, recurrence and survival were collected. OS was estimated according to the Kaplan-Meier method and compared between groups (gBRCA+and BRCA wild type, wt) by log-rank test. Cox regression model was used for univariate and multivariate analysis of factors associated with risk of death. Results: 100 patients with mTNBC were enrolled on the registry between 2011- 2018. For 100 patients, 20% (20/100) had de novo stage IV whereas 80% (80/100) had metastatic recurrence. 12% had gBRCA+ status; 72% were gBRCA wt type; and 16% had unknown gBRCA status. gBRCA+ patients were younger (49 vs. 57 years, p=0.02) but otherwise well matched to gBRCA wt including similar metastatic disease burden and prior treatments. No patients received a PARP inhibitor. With 31 months median follow-up, median overall survival was 21 months (95% CI [13-23] months) for all patients, 18 months (95% CI [15-27] months) for gBRCA wt patients and has not yet been reached for gBRCA+ patients (p=0.023). 3-year estimated OS is 63% in gBRCA+ versus 28% in gBRCA wt (p=0.02). On multivariate analysis, gBRCA+ was associated with reduced risk of death (HR=0.33; 95%CI [0.23-0.91], p=0.033). Conclusions: In patients with mTNBC gBRCA+ patients have a clinically significantly improved 3-year OS compared to gBRCA wt patients. Further research is needed to understand tumor and host biological reasons for this observation. As these patients are at risk for primary site progression and secondary breast and ovarian cancers, further research regarding the role of proactive surgical treatment in mTNBC with gBRCA mutation is warranted.
- Published
- 2019
18. LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates
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Kathleen M. Giacomini, Evan Augustyn, Claire Colas, Huan-Chieh Chien, Lawrence Lin, Christopher Hernandez, Arik A. Zur, Andrew Flint, Avner Schlessinger, Allen A. Thomas, Nathan Heeren, Logan Hansen, Sydney Miller, and Karissa Finke
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0301 basic medicine ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Carboxylic acid ,Medicinal & Biomolecular Chemistry ,Clinical Biochemistry ,Carboxylic Acids ,Pharmaceutical Science ,Large Neutral Amino Acid-Transporter 1 ,Phenylalanine ,Hydroxamic Acids ,Biochemistry ,SLC7A5 ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Drug Discovery ,Humans ,Tetrazole ,Molecular Biology ,Chromatography, High Pressure Liquid ,Acyl sulfonamide ,chemistry.chemical_classification ,Chromatography ,Hydroxamic acid ,Organic Chemistry ,Transporter substrate ,Pharmacology and Pharmaceutical Sciences ,Prodrug ,Amino acid ,030104 developmental biology ,HEK293 Cells ,Transporter inhibitor ,chemistry ,Blood-Brain Barrier ,High Pressure Liquid ,Molecular Medicine ,Bioisostere - Abstract
© 2016 Elsevier Ltd Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.
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- 2016
19. LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs
- Author
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Arik A. Zur, Claire Colas, Kathleen M. Giacomini, Huan-Chieh Chien, Evan Augustyn, Allen A. Thomas, Logan Hansen, Karissa Finke, Nathan Heeren, Avner Schlessinger, and Lawrence Lin
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0301 basic medicine ,Models, Molecular ,Phenylalanine hydroxylase ,Stereochemistry ,Medicinal & Biomolecular Chemistry ,Phenylalanine ,Clinical Biochemistry ,Pharmaceutical Science ,Large Neutral Amino Acid-Transporter 1 ,Negishi coupling ,Biochemistry ,SLC7A5 ,Article ,Dose-Response Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Medicinal and Biomolecular Chemistry ,Structure-Activity Relationship ,0302 clinical medicine ,Models ,Drug Discovery ,Aromatic amino acids ,Structure–activity relationship ,Humans ,Binding site ,Tyrosine ,Molecular Biology ,chemistry.chemical_classification ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Molecular ,Transporter substrate ,Pharmacology and Pharmaceutical Sciences ,Amino acid ,030104 developmental biology ,Transporter inhibitor ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Drug - Abstract
© 2016 Elsevier Ltd. All rights reserved. The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.
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- 2016
20. Clinical and biomarker results from phase I/II study of PI3K inhibitor BYL 719 (alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer
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Stephen K. Williamson, Stephanie LaFaver, Jecinta Scott, Marc Hoffmann, Qamar J. Khan, Bruce F. Kimler, Anne O'Dea, Jilliann A De Jong, Vandana G. Abramson, Julia Urban, Andrew K. Godwin, Sharon Lewis, Jaimie Heldstab, Greg Reed, Priyanka Sharma, Ziyan Y. Pessetto, Harsh B. Pathak, Manana Elia, Yen Y. Wang, and Karissa Finke
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,HER2 negative ,medicine.disease ,Metastatic breast cancer ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Phase i ii ,Oncology ,030220 oncology & carcinogenesis ,Concomitant ,Cancer research ,Medicine ,Biomarker (medicine) ,business ,PI3K/AKT/mTOR pathway ,Nab-paclitaxel - Abstract
1018Background: Activation of Phosphatidylinositol-3-kinase (PI3K) pathway may confer resistance to taxanes and in preclinical models concomitant inhibition of the PI3K pathway enhances efficacy of...
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- 2018
21. Comparison of outcomes for AJCC 8th Anatomic and Prognostic staging in contemporary triple negative breast cancer (TNBC) multisite registry
- Author
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Bruce F. Kimler, Rachel Yoder, Rajvi H. Shah, Jennifer R. Klemp, Priyanka Sharma, Marc Hoffmann, Lauren Nye, Qamar J. Khan, Sheshadri Madhusudhana, Anne O'Dea, Gregory James Crane, Yen Y. Wang, Karissa Finke, and Manana Elia
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,TNM staging system ,Stage (cooking) ,business ,Triple-negative breast cancer - Abstract
555Background: Eighth edition of the AJCC TNM staging system incorporates biological prognostic factors along with the traditional anatomical factors and currently Prognostic (P) stage must be used...
- Published
- 2018
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